Protein kinase Cɛ mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2)

Aziz, Moammir H.; Hafeez, Bilal Bin; Sand, Jordan M.; Pierce, David B.; Aziz, Saba; Dreckschmidt, Nancy E.; Verma, Ajit Kumar

doi:10.1038/onc.2010.63

Cited by 94 publications

(86 citation statements)

References 40 publications

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“…Signal transducers and activators of transcription 3 (Stat3) activation by PKC in glioma cells also stimulate cell invasion. These responses are found in not only glioma, but also several additional types of human cancer cells, including prostate, skin (melanoma), bladder, colon, lung, pancreatic, and breast [208]. Furthermore, galectin-1, a homodimeric adhesion molecule, is linked with the trafficking of 1-integrin, which is controlled by a PKC /vimentindependent pathway.…”

Section: Gastrointestinal Stromal Tumormentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes and Cancer

Kang

2014

New Journal of Science

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Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

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Section: Gastrointestinal Stromal Tumormentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes and Cancer

Kang

2014

New Journal of Science

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“…This notion is supported by studies in other cell types showing that novel PKC isoforms, such as PKC␦ and PKC⑀, can target this residue in STAT3. [38][39][40]50 Moreover, one study has demonstrated that PKC activation of CLL cells stimulates Mcl-1 expression, 51 and our own work indicates that PKC␦ and PKC⑀ are highly expressed in CLL cells. 26 In the present study, stimulation of CLL cells with bryostatin induced increased levels of pS 727 -STAT3 and Mcl-1 protein expression that was dependent on STAT3 activation; treatment of CLL cells with a STAT3 inhibitor before bryostatin stimulation inhibited induction of STAT3 phosphorylation and Mcl-1 expression.…”

Section: Discussionmentioning

confidence: 78%

“…[38][39][40] To investigate whether PKC is similarly involved in the regulation of Mcl-1 expression in CLL cells, we examined the effect of PKC inhibition on pS 727 -STAT3 levels and Mcl-1 expression. Figure 6A Figure 6C shows that IL-6R blockade had a small, but significant, additive effect on the inhibition of Mcl-1 expression when used in combination with BisI.…”

Section: Induction Of Ps 727 -Stat3 In Cll Cells By C-abl and Nf-b Rementioning

confidence: 99%

c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells

Allen

Talab

Zuzel

et al. 2011

Blood

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IntroductionChronic lymphocytic leukemia (CLL) is a malignant disease characterized by the gradual accumulation of mature, nonproliferative B cells expressing a distinctive group of surface markers, including CD19, CD23, and CD5. 1,2 It is a heterogeneous disease that can follow an indolent or aggressive course, and understanding the nature of this heterogeneity is an area of intense research interest. 2 CLL cells are resistant to apoptosis, and this is thought to be regulated by survival signals from the microenvironment coupled with intrinsic defects in apoptotic machinery. [3][4][5][6][7] Therefore, understanding in greater detail the molecular basis of such apoptotic resistance may help lead to the discovery of agents effective in CLL treatment.The more aggressive, poor prognostic course of CLL positively correlates with a series of cellular markers, such as ZAP70, CD38, and unmutated IgV H . [8][9][10] Recently, it has been reported that high expression levels of the antiapoptotic protein Mcl-1 in CLL cells correlate with both poor disease prognosis 11 and in vitro and in vivo chemoresistance. [11][12][13][14] Moreover, down-regulation of Mcl-1 using antisense oligonucleotides results in cell death during in vitro culture, 15 and elevated Mcl-1 protein expression has been shown to prolong the survival of CLL cells exposed to a variety of apoptosis-inducing stimuli. 16 Taken together, this evidence establishes Mcl-1 as a critical mediator of CLL cell survival.Another signaling protein overexpressed in CLL cells that plays a role in apoptotic resistance is the nonreceptor tyrosine kinase c-Abl. 17 c-Abl appears to be important for normal B-cell development because targeted disruption of the gene encoding this protein in mice results in development of lymphopenia. 18 c-Abl functions in B cells to phosphorylate CD19 after antigen engagement of the B-cell receptor (BCR), highlighting c-Abl as an important regulator of B-cell signaling. 19 In CLL, the overexpression of c-Abl stimulates activity of the nuclear factor-B (NF-B) pathway, leading to increased resistance of the malignant cells to spontaneous apoptosis. 17 Thus, a pathophysiologic role for this kinase in CLL is in the regulation of prosurvival signaling.Active NF-B is known to induce the autocrine expression of cytokines, such as interleukin-6 (IL-6). 20 IL-6 in CLL is associated with adverse disease features and reduced patient survival. 4 It is thought that elevated levels of IL-6 can promote disease progression either indirectly through effects on the microenvironment or directly through effects on cell survival and proliferation. An example of the direct effect of IL-6 is its capability of activating the transcription factor STAT3 via the classic IL-6 receptor (IL-6R) pathway. 21 Such stimulation of STAT3 then promotes up-regulation of antiapoptotic genes, such as Mcl-1. [22][23][24] A role for c-Abl in the activation of STAT3 has been described, 25 as well as a connection, in chronic myelogeneous leukemia (CML) cells, between c-Abl and Mcl-1. 21 Th...

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“…CTRP8‐RXFP1 is emerging as a new ligand–receptor system which promotes GBM migration (Glogowska et al ., 2013) and, as shown here, protects against the cytotoxic effects of the DNA alkylating drug TMZ. Likely initiated by an interaction of RXFP1 with the small G protein Gα i3 to activate the Gα i3 ‐Gβγ‐PI3K signaling pathway (Nguyen and Dessauer, 2005), our discovery of a novel CTRP8‐RXFP1‐STAT3 signaling cascade in human GBM links this CTRP8‐RXFP1 system to oncogenic STAT3 functional outcomes, including GBM cell survival, angiogenesis, and cell migration/invasion (Aziz et al ., 2010; Butler et al ., 2013; Ouedraogo et al ., 2017). CTRP8‐activated RXFP1 may utilize PI3K to mediate STAT3 activation as PI3K and its target BMX TEC kinase were recently shown to mediate the phosphorylation of STAT3 (Glogowska et al ., 2013; Hart et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

et al. 2018

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The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

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Protein kinase Cɛ mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2)

Cited by 94 publications

References 40 publications

Protein Kinase C (PKC) Isozymes and Cancer

Protein Kinase C (PKC) Isozymes and Cancer

c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

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